Background Severe malaria is a life-threatening disease with intravenous artesunate as the only recommended first line therapy. Global annual incidence of severe malaria is ~2 million cases with a case fatality rate >5% (despite antimalarial treatment) in endemic regions. Children under 5 years of age account for ~80% of all malaria deaths. Consequently, early evaluation of efficacy and safety in children <5 years of age is of paramount importance for the development of severe malaria therapies. KAE609 (Cipargamin) is a potent and fast-acting schizonticidal drug. Data are presented here from nonclinical juvenile toxicity studies with Cipargamin that supports early inclusion of paediatric patients in Phase II studies.

Methods Repeated-dose toxicity studies in juvenile animals were conducted to support enrolment of paediatric patients from 6 months to 12 years of age. The rat is a sensitive toxicological species, and parenteral administration was used for ease of administration to young animals and to maximize systemic exposure. Effects from birth through to sexual maturation were assessed by administration on days 4 to 11 or days 20 to 27 of age with ~3 months of recovery. Endpoints included clinical observations, assessments of sexual maturation, oestrous cycling and reproductive capacity, clinical pathology, toxicokinetic analyses and histopathology.

Results Toxicological findings for Cipargamin in juvenile rats were comparable with earlier toxicity studies in adult animals. No indication of developmental or reproductive risks were observed that preclude use of Cipargamin in paediatric patients.

Conclusion The juvenile toxicity studies fully assessed the nonclinical safety profile of Cipargamin and enable inclusion of the planned paediatric population in Phase II studies.

Funding: This project is part of the EDCTP2 program supported by the Wellcome Trust.